1. Field of the Invention
The compounds of the present invention belong to the class of antibacterial agents commonly called cephalosporins.
2. Description of the Prior Art
Sumitomo's West Germany Offenlegungsschrift No. 2,614,303 laid open Oct. 14, 1976 (and Japan Kokai No. 51-115491) describes cephalosporins having the general formula ##STR1## in which X is exemplified as acetoxy or a heterocyclic mercapto group such as 2-methyl-1,3,4-thiadiazol-5-yl, 1-methyl-tetrazol-5-yl and 1,2,3-triazol-5-yl.
Cephalosporins included under the general formula ##STR2## are described, for example, in U.S. Pat. No. 3,905,963 in which Examples II and VII are titled "Preparation of 7-[D(-)-.alpha.-aminophenylacetamido]-3-carbamoyloxymethyl-3-cephem-4-carb oxylic Acid" and "Preparation of Benzhydryl 7-[D(-)-.alpha.-(t-butoxycarbamido)phenylacetamido]-3-carbamoyloxymethyl-3 -cephem-4-carboxylate", respectively and Claim 1 reads
A process for preparing a compound having the formula ##STR3## which comprises the sequence of reacting a compound of the formula ##STR4## with an N-substituted isocyanate of the formula ##STR5## in which X is halogen, to produce a corresponding 3-(N-substituted) carbamoyloxymethyl derivative, and cleaving the N-substituent in the presence of silica gel, an aqueous buffer solution having a pH of from about 5 to about 9, an alkali or alkaline earth metal carbonate, bicarbonate, or sulfite, or zinc with a C.sub.1 -C.sub.4 alcohol or an acid having a pK value greater than about 3 to produce the desired 3-carbamoyloxymethyl cephalosporin derivative, in which, in the foregoing formulae, R.degree. is hydrogen or methoxy, R.sub.4 is hydrogen and R.sub.5 is C.sub.1 -C.sub.8 alkanoyl; azidoacetyl; cyanoacetyl; haloacetyl; ##STR6## in which Ar is phenyl, thienyl, furyl, pyrrolyl, or phenyl substituted with from one to three substituents selected from the group consisting of fluorine, chlorine, bromine iodine, trifluoromethyl, hydroxy, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, cyano, and nitro; ##STR7## in which Ar' is phenyl, pyridyl, or substituted phenyl as defined above, and Y is oxygen or sulfur; ##STR8## in which Ar is as defined above, and B is a hydroxyl or carboxyl group protected by esterification; --CH; --N.sub.3 ; or --NHR in which R is benzyloxycarbonyl, C.sub.1 -C.sub.4 alkoxycarbonyl, cycloalkoxycarbonyl, triphenylmethyl, ##STR9## or 2,2,2-trichloroethoxycarbonyl; (3-sydnone)C.sub.2 -C.sub.3 alkanoyl; ##STR10## in which R' is hydrogen or methoxy; 2-(1H-tetrazol-l-yl)acetyl; ##STR11## in which R" is as herein defined, and R.sup.3 is amino or an acylamido group in which the acyl group is C.sub.1 -C.sub.4 alkanoyl, C.sub.6 -C.sub.12 aroyl, C.sub.1 -C.sub.4 alkoxycarbonyl, benzyloxycarbonyl, C.sub.5 -C.sub.6 cycloalkoxycarbonyl, C.sub.6 -C.sub.12 aryloxycarbonyl, phthaloyl, or one of the above groups substituted with from one to three groups each selected from the group consisting of C.sub.1 -C.sub.4 alkyl, halo, nitro, C.sub.1 -C.sub.4 alkoxy, cyano; or R.sup.4 and R.sup.5 taken together with the nitrogen to which they are bonded is phthalimido or a cyclic imide moiety of a C.sub.3 -C.sub.12 dicarboxylic acid, and R" is hydrogen, an amine salt cation of dicyclohexylamine, triethylamine, or tributylamine, or a carboxy protecting group selected from the group consisting of C.sub.1 -C.sub.6 alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, C.sub.5 -C.sub.7 tert-alkenyl, C.sub.5 -C.sub.7 tert-alkynyl, benzyl, nitrobenzyl, tetrahydropyranyl, succinimidomethyl, phthalimidomethyl, methoxybenzyl, dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,5-trinitrophenyl, bis(p-methoxyphenyl)methyl, triphenylmethyl, benzhydryl, benzyloxymethyl, C.sub.2 -C.sub.6 alkanoyloxymethyl, C.sub.2 -C.sub.4 alkanoyl, phenacyl, and a radical of the formula ##STR12## in which each R.sup.2 independently is C.sub.1 -C.sub.4 alkyl or halo selected from the group consisting of bromo, chloro, fluoro, and iodo, subject to the limitation that at least one R.sup.2 is C.sub.1 -C.sub.4 alkyl.
Intermediates such as diphenylmethyl 7.beta.-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate and diphenylmethyl-7.beta.-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate and its toluene-p-sulfonic acid salt are among the compounds described in U.S. Pat. No. 3,966,717. Desacetylcephaloglycine is described in U.S. Pat. No. 3,560,489.
As additional examples, Derwent's Farmdoc abstract 38079X discloses compounds of the formula ##STR13## where Y=O or S; R.sub.1 = 1-20C organic radical; R.sub.2 = 1-3C alkyl or benzyl; R.sub.1 + R.sub.2 completes a 5, 6 or 7 membered ring opt. containing other hetero atoms; R.sub.3 = phenyl (opt. substd. by one or more hydroxy, halo, nitro, 1-3C alkoxy or amino), 2- or 3-thienyl, 3-7C cycloalkyl or 1-4C alkyl, and Farmdoc 59670X discloses compounds of the formula ##STR14## where R.sub.1 = H, a cation or a blocking group and R.sub.2 = acetoxy, carbamyloxy, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-methyl-1,2,3,4-tetrazol-5-ylthio.
U.S. Pat. No. 3,945,995 describes the preparation of the N-hydroxysuccinimido ester of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid.
Compounds included under the general formula ##STR15## are called cephamycins rather than cephalosporins. Well-known examples are cefoxitin and cephamycin C in which acyl represents ##STR16## respectively (see the Merck Index, Ninth Edition, Monograph numbers 1912 and 1940). For examples, see U.S. Pat. Nos. 3,775,410; 3,780,034; 3,780,037; and 3,887,549 (in which acyl includes 2-phenylglycyl and the like). For the latter compound (both with and without the 7-methoxy substituent) see also R. Nagarajan et al., J. Amer. Chem. Soc. 93, 2308-2310 (1971).